US8173804B2 - Process for production of mirtazapine - Google Patents
Process for production of mirtazapine Download PDFInfo
- Publication number
- US8173804B2 US8173804B2 US12/443,662 US44366208A US8173804B2 US 8173804 B2 US8173804 B2 US 8173804B2 US 44366208 A US44366208 A US 44366208A US 8173804 B2 US8173804 B2 US 8173804B2
- Authority
- US
- United States
- Prior art keywords
- mirtazapine
- propanol
- weight
- parts
- phenylpiperazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- QUVYCLFJDGCBLC-UHFFFAOYSA-N CN1CCN(C2=C(CO)C=CC=N2)C(C2=CC=CC=C2)C1.CN1CCN2C3=NC=CC=C3CC3=C(C=CC=C3)C2C1.O=S(=O)(O)O Chemical compound CN1CCN(C2=C(CO)C=CC=N2)C(C2=CC=CC=C2)C1.CN1CCN2C3=NC=CC=C3CC3=C(C=CC=C3)C2C1.O=S(=O)(O)O QUVYCLFJDGCBLC-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
Definitions
- the present invention relates to a process for production of mirtazapine, which is useful as an antidepressant. More specifically, the invention relates to a process for production of mirtazapine by cyclization of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol with concentrated sulfuric acid.
- Mirtazapine is a useful antidepressant compound, and it can be synthesized by cyclization of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol with concentrated sulfuric acid.
- Known methods for isolating mirtazapine include a method in which the cyclized reaction mixture is diluted with water and then alkalinized, and the produced precipitate is separated and then extracted with methylene chloride and concentrated to obtain crude mirtazapine (Patent document 1); a method in which the cyclized reaction mixture is diluted with water and then alkalinized and extracted in the presence of toluene, concentrated, and crystallized in a toluene-heptane system (Patent document 2); and a method in which the cyclized reaction mixture is diluted with water and then alkalinized, the produced precipitate is separated, the mother liquor is concentrated and both of the obtained residues are combined and suspended in isopropanol, after which extraction and concentration are performed to obtain
- Patent document 1 Japanese Patent Public Inspection No. 2004-500324
- Patent document 2 International Patent Publication No. WO 01/038330
- ICH Guideline methylene chloride and toluene are Class 2 solvents whose residues in pharmaceutical products are to be limited, and it is preferred to avoid the use of such solvents in the final stages of drug manufacturing.
- the invention is the following.
- [3] A production process according to [1] or [2] above, wherein heptane is added after the dilution is alkalinized.
- [4] A production process according to [3] above, wherein the amount of heptane used is 10-70 wt % with respect to the total of propanol and heptane.
- [5] A production process according to any one of [1] to [4] above, wherein the concentrated sulfuric acid is used at 300-400 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol for cyclization, and the obtained reaction mixture is diluted with water at 100-400 parts by weight with respect to 100 parts by weight of the reaction mixture.
- the extraction from the reaction mixture that has been diluted with water is carried out with propanol, which is a Class 3 solvent with low toxicity according to the ICH Guideline, and therefore the obtained mirtazapine can be safely used as a drug.
- reaction mixture that has been diluted with water is directly extracted using propanol under alkaline conditions, there is no need for a step of extraction after the mirtazapine precipitate that is produced has been isolated, and therefore the process is greatly simplified.
- the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol used as the starting material according to the invention can be synthesized by the method described in WO 01/23345 or WO 01/042240, for example.
- Mirtazapine (1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine; CAS Registry No.: 85650-52-88) is synthesized by cyclization of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol with concentrated sulfuric acid, as represented by the following formula.
- the concentrated sulfuric acid used is preferably 97-99% concentrated sulfuric acid.
- the amount of concentrated sulfuric acid used will normally be 300-400 parts by weight and is preferably 340-380 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- the reaction is carried out by addition of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol to the concentrated sulfuric acid.
- the temperature of the reaction mixture during addition is usually 0-50° C. and preferably 5-40° C. from the viewpoint of reducing heat release and limiting production of tar-like impurities.
- 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol is preferably carried out in portions (10-30 portions, for example) from the viewpoint of efficiently promoting the reaction.
- stirring is effected for 3-10 hours usually at about 20-50° C. and preferably at about 30-40° C., to accelerate the reaction.
- the sulfuric acid concentration of the reaction mixture is usually lowered by a method such as dropwise addition into water.
- the amount of water used is preferably 100-400 parts by weight with respect to 100 parts by weight of the reaction mixture.
- the liquid temperature of the diluent is preferably kept at about 0-30° C., from the viewpoint of reducing heat release and limiting production of impurities (tar).
- the decoloring agent may be decolorizing carbon or the like, and the decoloration may be carried out at 5-35° C. for 10-60 minutes.
- the decoloring agent is then filtered out and washed with usually 500-600 parts by weight of water with respect to 100 parts by weight of the decoloring agent.
- the decoloration is preferably carried out after adjusting the pH of the diluent.
- the pH will usually be no greater than 3, and is preferably 1-2.
- the present inventors have found, surprisingly, that it is important from the standpoint of increasing the purity for the decoloration to be carried out at no higher than pH 3.
- the pH adjustment is accomplished with an alkali.
- alkali there may be mentioned alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, with sodium hydroxide being preferred.
- the alkali is preferably added dropwise as an aqueous solution, to a concentration of 20-50 wt % and preferably 20-30 wt % from the viewpoint of manageability.
- the pH adjustment will usually be in a range of 5-50° C. and preferably 10-35° C.
- mirtazapine is extracted from an aqueous solution using propanol, which is a solvent of Class 3 with low toxicity according to the ICH Guideline and is normally miscible with water in any proportion, and this allows mirtazapine to be obtained at higher purity and in a safer form for use as a drug, than when the extraction is accomplished with methylene chloride or toluene.
- propanol which is a solvent of Class 3 with low toxicity according to the ICH Guideline and is normally miscible with water in any proportion
- the extraction with propanol is possible because the aqueous solution contains a large amount of inorganic salt due to the concentrated sulfuric acid and alkali.
- the propanol used may be either 1-propanol or 2-propanol.
- the amount of propanol used is preferably 130-500 parts by weight, more preferably 130-300 parts by weight and most preferably 130-200 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol. If the amount of propanol used is less than 130 parts by weight, the mirtazapine will not dissolve after alkalinization of the reaction mixture, thus preventing liquid separation, while if it is greater than 500 parts by weight, the extract may contain impurities (inorganic salt of the concentrated sulfuric acid and alkali, for example).
- the pH will normally be 8 or higher, and is preferably 10-12.
- the alkali used for this step may be the same alkali used for the aforementioned pH adjustment, and it is preferably added dropwise in the form of an aqueous solution, at a concentration of 20-50 wt % and preferably 20-30 wt % from the viewpoint of manageability.
- the temperature of the reaction mixture during pH adjustment will usually be 20-50° C.
- heptane is preferably added after alkalinization, for extraction with a propanol-heptane mixed solvent. This can minimize carry-in of water into the organic layer and is therefore advantageous for obtaining an anhydrate of mirtazapine, while also shortening the time required for distilling off of the solvent.
- the amount of heptane used is preferably 10-70 wt % and more preferably 50-70 wt % based on the total weight of the propanol and heptane.
- the extraction is carried out while heating the solution at 70-80° C., after which liquid separation is performed to remove the aqueous layer.
- Propanol or a propanol/heptane mixed solvent may be added to the organic layer next.
- the amount will normally be 350-1000 parts by weight and preferably 600-950 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- the amount of heptane is 10-60 wt % with respect to the total of propanol and heptane, and the amount of the mixed solvent is usually 350-1000 parts by weight and preferably 350-700 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- the solution may be subjected to dehydration treatment, and for example, a dehydrating agent such as anhydrous magnesium sulfate, anhydrous sodium sulfate or molecular sieves may be used.
- a dehydrating agent such as anhydrous magnesium sulfate, anhydrous sodium sulfate or molecular sieves may be used.
- the amount of dehydrating agent used will normally be 10-20 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- active alumina As decoloring agents there may be mentioned active alumina, decolorizing carbon and the like.
- Alumina A-11 product of Sumitomo Chemical Co., Ltd.
- the amount of active alumina used will normally be 5-30 parts by weight and preferably 10-20 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- Shirasagi A product of Takeda Pharmaceutical Co., Ltd.
- the amount of decolorizing carbon used will normally be 2-10 parts by weight and preferably 4-6 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- the alumina and decolorizing carbon may be used alone or in combination.
- the temperature for decoloration will normally be 15° C.-40° C. and preferably 20-35° C.
- the time required for decoloration is usually about 15-30 minutes.
- the decoloring agent is then filtered and washed with propanol.
- the amount of propanol used for washing will usually be 200-250 parts by weight with respect to 100 parts by weight as the total decoloring agent.
- the propanol or propanol/heptane mixed solvent is then distilled off.
- the solvent may be distilled off at atmospheric pressure or under reduced pressure.
- the degree of reduced pressure may be 0.6-40 kPa and preferably 4-30 kPa from the viewpoint of improving the distillation rate.
- the solvent is distilled off until the necessarily extent of crystallization occurs.
- 2-propanol the solvent is distilled off until the 2-propanol remains in the concentrate at 40-100 parts by weight and preferably 40-80 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- 1-propanol the solvent is distilled off until the 1-propanol remains in the concentrate at 40-100 parts by weight and preferably 40-60 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- Crystallization can be carried out directly from the obtained concentrate, or mirtazapine may instead be crystallized from a solvent of Class 3 of the ICH Guideline, water or a mixture thereof.
- heptane is preferably added for the crystallization.
- the amount of heptane will normally be 10-100 parts by weight and preferably 40-80 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- the temperature during the heptane addition is preferably 55-70° C. which will not cause deposition of the crystals.
- the heptane is preferably added dropwise.
- Seed crystals are preferably added so that the obtained solution has a uniform crystal size. They will usually be added at 48-55° C. The amount of seed crystals used will normally be 0.005-0.1 part by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- the crystals are then matured at 48-55° C. for about 1-2 hours and cooled.
- the cooling is preferably gradual cooling, for example at 0-10° C. for 1-10 hours and preferably 5-8 hours.
- the mirtazapine crystals are isolated by filtering and washed with heptane or the like.
- the amount of heptane used may be 30-100 parts by weight with respect to 100 parts by weight of the 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol.
- This convenient process allows production of mirtazapine at high purity and in a form safe for use as a drug.
- the pH was adjusted to 1.5 by dropwise addition of 635.8 g of an aqueous solution of 25% sodium hydroxide to the diluent at 13-30° C. After then adding 21 g of decolorizing carbon and stirring at 30-33° C. for 45 minutes, the mixture was filtered and washed with 108 g of water, and the filtrate was separated into 2 parts.
- the filtrate was concentrated under reduced pressure and the 2-propanol was distilled off to a concentrated residue of 38.5 g. After then adding 7.5 g of 2-propanol and heating to 66° C., 15 g of heptane was added. A small amount of mirtazapine seed crystals was added at about 53° C., and matured at 50° C. for 1 hour and then cooled to 1° C. over a period of 6 hours. The crystals were filtered out and washed with 14 g of heptane. They were then dried under reduced pressure at about 60° C. to obtain 21.2 g of mirtazapine as white crystals. The yield was 80% and the HPLC purity was 99.98%.
- Example 2 To 699 g of the remainder of the filtrate that had been separated into two parts in Example 1 there was added 51 g of 1-propanol, and then a 25% sodium hydroxide aqueous solution was added dropwise at 22-30° C. to pH 11.8 (54.1 g of solution used). The liquid separation was performed at a temperature of approximately 76° C. After then adding 170 g of 1-propanol to the organic layer and cooling to approximately 27° C., 4.8 g of alumina A-11 (product of Sumitomo Chemical Co., Ltd.) was added, the mixture was stirred at about 23° C. for 15 minutes, 1.4 g of decolorizing carbon was added and the mixture was stirred for 15 minutes.
- alumina A-11 product of Sumitomo Chemical Co., Ltd.
- the decoloring agent was washed with 14.2 g of 1-propanol.
- the filtrate was concentrated under reduced pressure at approximately 70° C. and the 1-propanol was distilled off to a concentrated residue of 37.1 g.
- 16 g of heptane was added.
- a small amount of mirtazapine seed crystals was added at about 48° C. and matured at about 50° C. for 1 hour, and then cooled to 1° C. over a period of 6 hours.
- the crystals were filtered out and washed with 14 g of heptane. They were then dried under reduced pressure at about 60° C. for 1 hour to obtain 19.6 g of mirtazapine as white crystals.
- the yield was 73.9% and the HPLC purity was 99.97%.
- the pH was adjusted to 1-2 by dropwise addition of an aqueous solution of 25% sodium hydroxide to the diluent at 13-30° C. After then adding 10 g of decolorizing carbon and stirring at 30-31° C. for 40 minutes, the mixture was filtered and washed with 54 g of water.
- the filtrate was concentrated under atmospheric pressure to a concentrated residue of 38.2 g.
- a small amount of mirtazapine seed crystals was added at about 53° C. and matured for 2 hours, and then cooled to about 1° C.
- the crystals were filtered out and washed with 14 g of heptane. They were then dried under reduced pressure at about 60° C. to obtain 21.2 g of mirtazapine as white crystals.
- the yield was 80% and the HPLC purity was 99.98%.
- mirtazapine from a reaction mixture obtained by cyclization of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol with concentrated sulfuric acid, at high purity and in a form suitable for safe use as a drug.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007-075573 | 2007-03-22 | ||
JPP2007-075573 | 2007-03-22 | ||
JP2007075573A JP5192707B2 (ja) | 2007-03-22 | 2007-03-22 | ミルタザピンの製造方法 |
PCT/JP2008/054628 WO2008114691A1 (ja) | 2007-03-22 | 2008-03-13 | ミルタザピンの製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
US20100029934A1 US20100029934A1 (en) | 2010-02-04 |
US8173804B2 true US8173804B2 (en) | 2012-05-08 |
Family
ID=39765800
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/443,662 Expired - Fee Related US8173804B2 (en) | 2007-03-22 | 2008-03-13 | Process for production of mirtazapine |
Country Status (16)
Country | Link |
---|---|
US (1) | US8173804B2 (ko) |
EP (1) | EP2135870B1 (ko) |
JP (1) | JP5192707B2 (ko) |
KR (1) | KR101418620B1 (ko) |
CN (1) | CN101541798B (ko) |
AT (1) | ATE555114T1 (ko) |
AU (1) | AU2008227637B2 (ko) |
BR (1) | BRPI0805835A2 (ko) |
CA (1) | CA2664286A1 (ko) |
DK (1) | DK2135870T3 (ko) |
ES (1) | ES2386165T3 (ko) |
IL (1) | IL197572A (ko) |
PL (1) | PL2135870T3 (ko) |
PT (1) | PT2135870E (ko) |
WO (1) | WO2008114691A1 (ko) |
ZA (1) | ZA200901559B (ko) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10603272B2 (en) | 2015-02-27 | 2020-03-31 | Kindred Biosciences, Inc. | Stimulation of appetite and treatment of anorexia in dogs and cats |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6452575B2 (ja) * | 2015-08-19 | 2019-01-16 | 株式会社トクヤマ | ミルタザピンの製造方法 |
JP6571497B2 (ja) * | 2015-11-13 | 2019-09-04 | 株式会社トクヤマ | ミルタザピンの製造方法 |
JP2017088564A (ja) * | 2015-11-13 | 2017-05-25 | 株式会社トクヤマ | ミルタザピンの製造方法 |
JP7018840B2 (ja) * | 2018-07-04 | 2022-02-14 | 住友化学株式会社 | フェニルピペラジンピリジンメチルアセテートの製造方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4062848A (en) | 1975-04-05 | 1977-12-13 | Akzona Incorporated | Tetracyclic compounds |
WO2000062782A1 (en) | 1999-04-19 | 2000-10-26 | Teva Pharmaceutical Industries Ltd. | Novel synthesis and crystallization of piperazine ring-containing compounds |
WO2001038329A1 (fr) | 1999-11-24 | 2001-05-31 | Sumika Fine Chemicals Co., Ltd. | Cristaux de mirtazapine anhydre et leur procede d'obtention |
US20020065413A1 (en) | 2000-11-27 | 2002-05-30 | Sumika Fine Chemicals Co., Ltd. | Anhydrous mirtazapine and process for preparing the same |
WO2005005410A1 (en) | 2003-07-10 | 2005-01-20 | Akzo Nobel N.V. | A method for the preparation of enantiomerically pure mirtazapine |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6545149B2 (en) | 1999-04-19 | 2003-04-08 | Teva Pharmaceutical Industries Ltd. | Synthesis and crystallization of piperazine ring-containing compounds |
US6434049B1 (en) * | 2000-12-29 | 2002-08-13 | Intel Corporation | Sample and hold voltage reference source |
-
2007
- 2007-03-22 JP JP2007075573A patent/JP5192707B2/ja not_active Expired - Fee Related
-
2008
- 2008-03-13 PL PL08722032T patent/PL2135870T3/pl unknown
- 2008-03-13 EP EP08722032A patent/EP2135870B1/en not_active Not-in-force
- 2008-03-13 ES ES08722032T patent/ES2386165T3/es active Active
- 2008-03-13 DK DK08722032.3T patent/DK2135870T3/da active
- 2008-03-13 WO PCT/JP2008/054628 patent/WO2008114691A1/ja active Application Filing
- 2008-03-13 AT AT08722032T patent/ATE555114T1/de active
- 2008-03-13 KR KR1020097006525A patent/KR101418620B1/ko active IP Right Grant
- 2008-03-13 BR BRPI0805835-0A patent/BRPI0805835A2/pt not_active IP Right Cessation
- 2008-03-13 AU AU2008227637A patent/AU2008227637B2/en not_active Ceased
- 2008-03-13 CA CA002664286A patent/CA2664286A1/en not_active Abandoned
- 2008-03-13 CN CN2008800007408A patent/CN101541798B/zh not_active Expired - Fee Related
- 2008-03-13 PT PT08722032T patent/PT2135870E/pt unknown
- 2008-03-13 US US12/443,662 patent/US8173804B2/en not_active Expired - Fee Related
-
2009
- 2009-03-04 ZA ZA2009/01559A patent/ZA200901559B/en unknown
- 2009-03-12 IL IL197572A patent/IL197572A/en not_active IP Right Cessation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4062848A (en) | 1975-04-05 | 1977-12-13 | Akzona Incorporated | Tetracyclic compounds |
WO2000062782A1 (en) | 1999-04-19 | 2000-10-26 | Teva Pharmaceutical Industries Ltd. | Novel synthesis and crystallization of piperazine ring-containing compounds |
JP2004500324A (ja) | 1999-04-19 | 2004-01-08 | テバ ファーマシューティカル インダストリーズ リミティド | ピペラジン環含有化合物の新規の合成及び結晶化 |
WO2001038329A1 (fr) | 1999-11-24 | 2001-05-31 | Sumika Fine Chemicals Co., Ltd. | Cristaux de mirtazapine anhydre et leur procede d'obtention |
WO2001038330A1 (fr) | 1999-11-24 | 2001-05-31 | Sumika Fine Chemicals Co., Ltd. | Cristaux de mirtazapine anhydres et leur procede de fabrication |
US20040138447A1 (en) | 1999-11-24 | 2004-07-15 | Sumika Fine Chemicals Co., Ltd. | Anhydrous mirtazapine crystals and process for preparing the same |
US20020065413A1 (en) | 2000-11-27 | 2002-05-30 | Sumika Fine Chemicals Co., Ltd. | Anhydrous mirtazapine and process for preparing the same |
WO2005005410A1 (en) | 2003-07-10 | 2005-01-20 | Akzo Nobel N.V. | A method for the preparation of enantiomerically pure mirtazapine |
Non-Patent Citations (2)
Title |
---|
Frans M. Kaspersen et al., "The Synthesis of Org 3770 Labelled with3 H, 13C and 14C", Journal of Labelled Compounds and Radiopharmaceuticals, vol. XXVII, No. 9 Feb. 24, 1989, pp. 1055-1068. |
International Preliminary Report on Patentability dated Oct. 1, 2009 issued in the corresponding International Application No. PCT/JP2008/054628. |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10603272B2 (en) | 2015-02-27 | 2020-03-31 | Kindred Biosciences, Inc. | Stimulation of appetite and treatment of anorexia in dogs and cats |
Also Published As
Publication number | Publication date |
---|---|
EP2135870B1 (en) | 2012-04-25 |
PT2135870E (pt) | 2012-05-11 |
IL197572A0 (en) | 2009-12-24 |
ZA200901559B (en) | 2010-02-24 |
EP2135870A4 (en) | 2011-06-08 |
DK2135870T3 (da) | 2012-07-16 |
JP2008231062A (ja) | 2008-10-02 |
EP2135870A1 (en) | 2009-12-23 |
KR20090121270A (ko) | 2009-11-25 |
ES2386165T3 (es) | 2012-08-10 |
US20100029934A1 (en) | 2010-02-04 |
BRPI0805835A2 (pt) | 2011-08-30 |
CN101541798B (zh) | 2011-09-14 |
ATE555114T1 (de) | 2012-05-15 |
KR101418620B1 (ko) | 2014-07-14 |
AU2008227637A1 (en) | 2008-09-25 |
PL2135870T3 (pl) | 2012-07-31 |
WO2008114691A1 (ja) | 2008-09-25 |
CA2664286A1 (en) | 2008-09-25 |
CN101541798A (zh) | 2009-09-23 |
AU2008227637B2 (en) | 2012-02-16 |
JP5192707B2 (ja) | 2013-05-08 |
IL197572A (en) | 2013-03-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8173804B2 (en) | Process for production of mirtazapine | |
CN1298324C (zh) | 萘啶衍生物、其制备方法及其作为磷酸二酯酶同功酶4(pde4)抑制剂的应用 | |
CA2700835C (en) | Solid forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)phenyl)propanoate and methods of their use | |
US8884033B2 (en) | Process for preparing aminobenzoylbenzofuran derivatives | |
RU2435775C2 (ru) | СИНТЕЗ 2-МЕТИЛ-4-(4-МЕТИЛ-1-ПИПЕРАЗИНИЛ)-10H-ТИЕНО[2,3-b] [1,5]БЕНЗОДИАЗЕПИНА И ЕГО СОЛЕЙ | |
WO2019241278A1 (en) | Substituted heterocycle fused gamma-carbolines synthesis | |
JP2008516005A (ja) | レトロゾールの改良された調製方法 | |
WO2009010988A1 (en) | An improved, industrially viable process for the preparation of high purity paliperidone | |
US8492551B2 (en) | Process for preparing an optically active proton pump inhibitor | |
JP2015500325A (ja) | (5−フルオロ−2−メチル−3−キノリン−2−イルメチル−インドール−1−イル)−酢酸エステルの製造のための方法 | |
CA2877445A1 (en) | Novel indazoles for the treatment and prophylaxis of respiratory syncytial virus infection | |
CA3121631A1 (en) | Substituted heterocycle fused gamma-carbolines synthesis | |
NO179517B (no) | Fremgangsmåte for fremstilling av 8-klorkinolonderivater | |
EP1435359A1 (en) | A process for the purification of roxithromycin | |
KR101485418B1 (ko) | 고순도 미르타자핀의 제조방법 | |
WO2012113325A1 (zh) | 一种制备氨氯地平的方法 | |
EP3902779B1 (en) | Process for the preparation exo-tert-butyl n-(3-azabicyclo[3.2.1]octan-8-yl)carbamate | |
WO2005070939A1 (en) | Synthesis of olanzapine and intermediates thereof | |
CN103159673A (zh) | 一种制备吉美嘧啶的精制方法 | |
KR20150044559A (ko) | 3-아미노-9,13b-디하이드로-1H-디벤즈-[c,f]이미다조[1,5-a]-아제핀 브롬산염의 신규 제조방법 | |
EP2768807B1 (en) | Processes for the preparation of 6-chloro-2,3,4,9-tetrahydro-1h-carbazole-1-carboxamide and of its precursors | |
WO2023109918A1 (zh) | 含氮杂环化合物、其制备方法及其用途 | |
JPH02268185A (ja) | 5―メチル―7―(ジエチルアミノ)―S―トリアゾロ(1,5―a)ピリミジン及びその酸付加塩の製造方法 | |
JP2003096075A (ja) | キノロンカルボン酸誘導体の製法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SUMITOMO CHEMICAL COMPANY, LIMITED,JAPAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MAEDA, CHIHARU;MAEDA, TAKUMA;SIGNING DATES FROM 20090227 TO 20090303;REEL/FRAME:022496/0933 Owner name: SUMITOMO CHEMICAL COMPANY, LIMITED, JAPAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MAEDA, CHIHARU;MAEDA, TAKUMA;SIGNING DATES FROM 20090227 TO 20090303;REEL/FRAME:022496/0933 |
|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20160508 |